0918 Edaravone (Radicava) (3)

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Edaravone (Radicava)

Proprietary

Policy History

Last Review

07/21/2020

Effective: 07/21/2017

Next

Review: 10/28/2021

Review History

Definitions

Additional Information

Clinical Policy Bulletin

Notes

Number: 0918

Policy *Please see amendment forPennsylvaniaMedicaid

at the end of this CPB.

Notes: PRECERTIFICATION REQUIRED

Precertification of edaravone is required of all Aetna

participating providers and members in applicable plan

designs. For precertification of edaravone, call (866) 752-7021

(Commercial), (866) 503-0857 (Medicare), or fax (866) 267

3277.

Site of Care Utilization Management Policy applies. For

information on site of service for edaravone, see Utilization

Management Policy on Site of Care for Specialty Drug

Infusions (https://www.aetna.com/health-care

professionals/utilization-management/drug-infusion-site

of-care-policy.html).

Aetna considers edaravone (Radicava) medically necessary

for the treatment of individuals with amyotrophic lateral

sclerosis (ALS) when all the following criteria are met:

▪ Diagnosis of definite or probable ALS; and

https://www.aetna.com/

https://www.aetna.com/health-care-professionals/utilization-management/drug-infusion-site-of-care-policy.html




▪ Member has scores of at least 2 points on all 12 areas of

the revised ALS Functional Rating Scale (ALSFRS-R); and

▪ Continuous use of ventilatory support during the day

and night is not required (noninvasive or invasive).

Aetna considers edaravone experimental and investigational

for the following (not an all-inclusive list):

▪ Acute encephalopathy

▪ Acute ischemic stroke

▪ Acute kidney injury

▪ Acute lung injury

▪ Acute pancreatitis-induced pancreatic and intestinal

injury

▪ Alzheimer's disease

▪ Asthma

▪ Autoimmune thyroiditis

▪ Brain radionecrosis

▪ Choroidal neovascularization

▪ Cisplatin-induced chronic renal injury

▪ Doxorubicin-induced cardiotoxicity / nephrotoxicity

▪ Intra-cerebral hemorrhage

▪ Multiple sclerosis

▪ Myocardial damage after ischemia and re-perfusion

▪ Nephropathy

▪ Osteoarthritis

▪ Parkinson disease

▪ Post-stroke depression

▪ Rheumatoid arthritis

▪ Seizure

▪ Stroke

▪ Subarachnoid hemorrhage

▪ Traumatic brain injury

▪ Wound healing.

Continuation Criteria

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Aetna considers continued use of edaravone medically

necessary when the following criteria are met:

▪ Diagnosis of definite or probable ALS; and

▪ There is a clinical benefit from edaravone therapy; and

▪ Invasive ventilation is not required.

Dosing Recommendations

The recommended dosage of edaravone (Radicava) is 60 mg

administered as an IV infusion over 60 minutes as follows:

Initial treatment cycle: Daily dosing for 14 days followed by a

14-day drug-free period

Subsequent treatment cycles: Daily dosing for 10 days out of

14-day periods, followed by 14-day drug-free periods.

Source: MT Pharma America 2019.

Background

Acute Encephalopathy

Hayakawa and colleagues (2020) noted that treatments for

pediatric acute encephalopathy are largely empiric with limited

evidence to support. These investigators examined recent

trends in clinical practice patterns for pediatric acute

encephalopathy at a national level. Discharge records were

extracted for children with acute encephalopathy from 2010 to

2015 using a national inpatient database in Japan. They

ascertained the secular trends in medications, diagnostic and

therapeutic procedures, healthcare costs, in-hospital mortality,

and length of hospital stays (LOS), using mixed effect linear or

logistic regression models. These researchers also

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ascertained variations and clustering of the practice patterns

across different hospitals using hierarchical cluster analyses.

A total of 4692 eligible inpatients were identified, these

investigators observed increasing trends in hospitalization

costs, corticosteroid and edaravone use and a decreasing

trend in LOS. Despite changes in treatments, the rates of

home respiratory support and in-hospital mortality were

constant during the study period. Hierarchical cluster analyses

showed that 6 hospital groups showed largely different

therapeutic strategies to the same disease regardless of

mortality rates. Hospitals with more intensive treatment

practices were likely to have higher mortality, while hospitals

with less intensive treatment practices were likely to have the

lower mortality. However, hospitals in one group (group 1)

had less intensive treatment practice even though they had the

highest mortality. The authors provided novel insights into the

recent trends in treatments for pediatric acute encephalopathy;

therapeutic strategies varied among hospitals, suggesting the

importance of pursuing evidence-based therapeutic strategy

and promoting standardized practices to pediatric acute

encephalopathy.

Furthermore, UpToDate reviews on “Acute toxic-metabolic

encephalopathy in children” (Chiriboga, 2019) and “Clinical

features, diagnosis, and treatment of neonatal

encephalopathy” (Wu, 2019) do not mention edaravone as a

therapeutic option.

Acute Kidney Injury

In a rat resuscitation model, Fu and colleagues (2020)

examined if edaravone (5-methyl-2-phenyl-2,4-dihydro-3H

pyrazol3-one, EDR) can ameliorate renal warm ischemia

reperfusion injury (IRI) by modulating endoplasmic reticulum

stress (ERS) and its down-stream effector after cardiac arrest

(CA) and cardiopulmonary resuscitation (CPR). Rats (n = 10)

experienced anesthesia and intubation followed by no CA

inducement were defined as the sham group. Trans-

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esophageal alternating current stimulation was employed to

establish 8-min of CA followed by conventional CPR for a

resuscitation model. The rats with successful restoration of

spontaneous circulation (ROSC) randomly received EDR (3

mg/kg, EDR group, n = 10) or equal volume normal saline

solution (the NS group, n = 10). At 24 hours after ROSC,

serum creatinine (SCR), blood urea nitrogen (BUN) levels, and

cystatin-C (Cys-C) levels were determined and the protein

level of glucose-regulated protein (GRP78), C/EBP

homologous protein (CHOP), extracellular signal-regulated

kinase (ERK), phosphorylated extracellular signal-regulated

kinase 1/2 (p-ERK1/2), Bax/Bcl-2, and caspase-3 were

detected by Western blot method. At 24 hours after ROSC,

SCR, BUN and Cys-C were obviously increased and the

proteins expression, including GRP78, CHOP and p-ERK1/2,

cleaved-caspase 3 Bax/Bcl-2 ratio, were significantly up-

regulated in the NS group compared with the sham group (p <

0.05). The remarkable improvement of these adverse

outcomes was observed in the EDR group (p < 0.05). The

authors concluded that EDR ameliorated renal warm IRI by

down-regulating ERS and its down-stream effectors in a rat

AKI model evoked by CA/CPR. These data may provide

evidence for future therapeutic benefits of EDR against acute

kidney injury (AKI) induced by CA/CPR.

Acute Lung Injury

Kassab and colleagues (2020) stated that EDR is a potent free

radical scavenger that has a promising role in combating many

acute lung injuries. Ischemia/reperfusion (i/R) process is a

serious condition that may lead to multiple-organ dysfunctions.

These investigators examined the novel mechanisms

underlying I/R-induced lung injury and assessed the protective

role of EDR. A total of 30 adult male rats were divided into 3

experimental groups: operated with no ischemia (sham-group),

I/R group, and EDR-I/R group. Hind-limb ischemia was carried

out by clamping the femoral artery. After 2 hours of ischemia

for the hind-limb, the rat underwent 24-hour of reperfusion.

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Rats in the EDR-I/R group received EDR (3 mg/kg), 30 mins

before induction of ischemia. At the end of the I/R trial,

specimens from the lungs were processed for histological,

immunohistochemical, enzyme assay, and RT-qPCR studies.

Specimens from I/R group showed focal disruption of the

alveolar architecture. Extensive mononuclear cellular

infiltration particularly with neutrophils and dilated congested

blood capillaries were observed. A significant increase in

inducible nitric oxide synthase (iNOS), nuclear factor-κB

(NFκB), and cyclooxygenase-2 (COX-2) immunoreaction was

detected and confirmed by RT-qPCR. Ultra-structural

examination showed red blood cells (RBCs) and fluid inside

alveoli, cellular infiltration, and vacuolations of the inter-

alveolar septum. In contrast, minimal changes were observed

in rats that received EDR before the onset of the ischemia.

The authors concluded that EDR exerted a potent protective

effect against lung injury induced by a hind-limb I/R in rats

through its antioxidant and anti-inflammatory activities.

Acute Pancreatitis-Induced Pancreatic and Intestinal Injury

Wang and Lin (2020) noted that acute pancreatitis (AP) is a

type of acute surgical abdominal disease in the world. It

causes intestinal damage with subsequent bacterial migration,

endotoxemia and secondary pancreatic infections. These

investigators examined if EDR could reduce pancreatic and

intestinal injury after AP in mice. This was demonstrated by a

reduction in histological score, apoptosis, interleukin (IL)-6, IL

1β and tumor necrosis factor-alpha (TNF-α), along with

obstructing activation of Toll-like receptor 4 (TLR4) and NFκB.

The authors concluded that the findings of this study

suggested that EDR exerted its protective effects against

pancreatic and intestinal injury after AP via regulation of the

TLR4/NFκB pathway. These researchers stated that the

findings provided the basis for EDR to treat AP-induced

pancreatic and intestinal injury, even might develop as a

potential therapy for other inflammatory diseases.

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Acute Stroke (e.g., Acute Ischemic Stroke and Intra-Cerebral Hemorrhage)

Yang and colleagues (2015) evaluated the effectiveness of

edaravone for acute stroke including acute ischemic stroke

(AIS) and intra-cerebral hemorrhage (ICH). These

investigators identified RCTs with comprehensive searches

and performed systematic reviews according to the Cochrane

methods of systematical reviews. Edaravone can reduce the

rate of death or long-term disability significantly for AIS

(relative risk [RR] = 0.65; 95 % confidence intervals [CI]: 0.48

to 0.89, p = 0.007). However, sensitivity analysis yielded a

different result. Edaravone can also improve the short-term

neurological impairment of AIS (mean difference (MD) = 7.09;

95 % CI: 5.12 to 9.05, p < 0.00001), and ICH (MD = -4.32; 95

% CI: -5.35 to -3.29, p < 0.00001). The authors concluded that

edaravone is beneficial in improving neurological impairment

resulting from AIS and ICH. However, there is currently

insufficient evidence that edaravone reduces death or long

term disability for AIS and ICH.

Bao and associates (2018) stated that cerebral vasculature

and neuronal networks will be largely destroyed due to the

oxidative damage by over-produced reactive oxygen species

(ROS) during a stroke, accompanied by the symptoms of

ischemic injury and blood-brain barrier (BBB) disruption. Ceria

nanoparticles, acting as an effective and recyclable ROS

scavenger, have been shown to be highly effective in neuro

protection. However, the brain access of nanoparticles can

only be achieved by targeting the damaged area of BBB,

leading to the disrupted BBB being unprotected and to

turbulence of the micro-environment in the brain.

Nevertheless, the integrity of the BBB will cause very limited

accumulation of therapeutic nanoparticles in brain lesions.

This dilemma is a great challenge in the development of

efficient stroke nano-therapeutics. These researchers

developed an effective stroke treatment agent based on

monodisperse ceria nanoparticles, which were loaded with

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edaravone and modified with Angiopep-2 and poly(ethylene

glycol) on their surface (E-A/P-CeO2). The as-designed

E-A/P-CeO2 features highly effective BBB crossing via

receptor-mediated transcytosis to access brain tissues and

synergistic elimination of ROS by both the loaded edaravone

and ceria nanoparticles. As a result, the E-A/P-CeO2 with low

toxicity and excellent hemo-/histo-compatibility can be used to

effectively treat strokes due to great intra-cephalic uptake

enhancement and, in the meantime, effectively protect the

BBB, holding great potentials in stroke therapy with much

mitigated harmful side effects and sequelae.

Oguru and co-workers (2018) noted that argatroban is a

thrombin inhibitor agent for acute non-cardioembolic ischemic

stroke in Japan. These researchers studied the prognosis in

patients with acute stroke treated by argatroban in comparison

with the control group with ozagrel. A total of 513 patients with

acute non-cardioembolic ischemic stroke were enrolled

retrospectively from the authors’ hospital database. Of all

patients with stroke, 353 were administered with argatroban.

The other 160 control patients were administered with

ozagrel. Patients were examined as to their stroke types, the

neurological severity according to the National Institutes of

Health Stroke Scale (NIHSS), and clinical outcomes on

discharge were determined according to the modified Rankin

Scale (mRS). A total of 353 patients with acute non

cardioembolic stroke, including 138 with lacunar infarction

(LIs) and 215 with athero-thrombotic infarction (ATI) showed

functional recovery by argatroban, but the effectiveness of

argatroban was not superior to ozagrel therapy defined by the

control group. A total of 255 patients with ATI who were

treated with both argatroban and ozagrel showed improvement

by 1 point. These investigators could not find any significant

difference between argatroban and ozagrel in the 2 stroke

subtypes, LI and ATI. They also found that combination

therapy of argatroban and edaravone was not superior to

argatroban monotherapy in clinical outcome. The authors

concluded that argatroban therapy was not superior to control

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with ozagrel therapy in acute non-cardioembolic ischemic

stroke, including LI and ATI, regardless of the use of

edaravone.

Naganuma and associates (2018) stated that uric acid (UA),

an anti-oxidant with neuroprotective effects, favorably affects

stroke outcome. However, the effect has not been examined

in patients treated with edaravone, a frequently used free

radical scavenger. These investigators examined if the use of

edaravone affected the relationship between UA levels and

outcome in acute ischemic stroke (AIS). They retrospectively

evaluated 1,114 consecutive ischemic stroke patients with pre

morbid mRS scores of less than 2 admitted within 24 hours of

onset (mean age of 74 years; median UA levels, 333 μmol/L).

These researchers divided the patients into 2 groups using the

median UA value as a cut-off, a low UA group (less than or

equal to 333 μmol/L; n = 566) and a high UA group (greater

than 333 μmol/L; n = 548), and compared their clinical

characteristics and favorable outcomes (mRS less than 2) at

90 days. These researchers examined the associations

between UA levels and 90-day stroke outcome in patients with

and without edaravone treatment. The high UA group had a

higher proportion of men, hypertension, atrial fibrillation, and

cardio-embolic stroke than the low UA group. The high UA

group also had a higher proportion of patients with mRS of

less than 2 at 90 days (61.5 versus 54.1 %, p = 0.013), but the

significance was diminished in multi-variate analysis (OR 1.30,

95 % CI: 0.94 to 1.71). In subgroup analysis, the high UA

group without edaravone exhibited a higher proportion of

patients with mRS of less than 2 at 90 days than the low UA

group (OR 2.87, 95 % CI: 1.20 to 7.16). The high UA group

with edaravone did not exhibit this difference. The authors

concluded that in AIS, the favorable association between high

UA levels and outcome at 90 days was not evident in patients

treated with edaravone.

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Kobayashi and colleagues (2019) examined the effect of

edaravone on neurological symptoms in patients with ischemic

stroke stratified by stroke subtype. Subjects were 61,048

patients aged 18 years or older who were hospitalized for less

than or equal to 14 days after onset of an AIS and were

registered in the Japan Stroke Data Bank, a hospital-based

multi-center stroke registration database, between June 2001

and July 2013. Patients were stratified according to ischemic

stroke subtype (large-artery atherosclerosis, cardio-embolism,

small-vessel occlusion, and cryptogenic/undetermined) and

then divided into 2 groups (edaravone-treated and no

edaravone). Neurological symptoms were evaluated using the

NIHSS. The primary outcome was changed in neurological

symptoms during the hospital stay (ΔNIHSS=NIHSS score at

discharge-NIHSS score at admission). Data were analyzed

using multi-variate linear regression with inverse probability of

treatment weighting after adjusting for the following

confounding factors: age, gender, and systolic and diastolic

blood pressure at the start of treatment, NIHSS score at

admission, time from stroke onset to hospital admission, infarct

size, co-morbidities, concomitant medication, clinical

department, history of smoking, alcohol consumption, and

history of stroke. After adjusting for potential confounders, the

improvement in NIHSS score from admission to discharge was

greater in the edaravone-treated group than in the no

edaravone group for all ischemic stroke subtypes (mean [95 %

CI] difference in ΔNIHSS: -0.46 [-0.75 to -0.16] for large-artery

atherosclerosis, -0.64 [-1.09 to -0.2] for cardio-embolism, and

-0.25 [-0.4 to -0.09] for small-vessel occlusion). The authors

concluded that for any ischemic stroke subtype, edaravone

use (compared with no use) was associated with a greater

improvement in neurological symptoms, although the

difference was small (less than 1 point NIHSS) and of limited

clinical significance.

Alzheimer's Disease

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Parikh and associates (2018) stated that Alzheimer's disease

(AD) is a devastating neurodegenerative disorder that lacks

any disease-modifying drug for the prevention and treatment.

Edaravone (EDR), an approved free radical scavenger, has

proven to have potential against AD by targeting multiple key

pathologies including amyloid-beta (Aβ), tau phosphorylation,

oxidative stress, and neuro-inflammation. To enable its oral

use, novel edaravone formulation (NEF) was previously

developed. These researchers evaluated the safety and

efficacy of NEF by using in-vitro/in-vivo disease model. In-vitro

therapeutic potential of NEF over EDR was studied against the

cytotoxicity induced by copper metal ion, H2O2 and Aβ42

oligomer, and cellular uptake on SH-SY5Y695 amyloid-β

precursor protein (APP) human neuroblastoma cell line. For i-

vivo safety and efficacy assessment, a total of 7 groups of

APP/PS1 (5 treatment groups, 1 each as a basal and sham

control) and 1 group of C57BL/6 mice as a positive control for

behavior tests were used; 3 groups were orally treated for 3

months with NEF at an equivalent dose of EDR 46, 138, and

414 µmol/kg, whereas 1 group was supplied with each

Donepezil (5.27 µM/kg) and Soluplus (amount present in NEF

of 414 µmol/kg dose of EDR). Behavior tests were conducted

to assess motor function (open-field), anxiety-related behavior

(open-field), and cognitive function (novel objective recognition

test, Y-maze, and Morris water maze). For the safety

assessment, general behavior, adverse effects, and mortality

were recorded during the treatment period. Moreover,

biochemical, hematological, and morphological parameters

were determined. Compared to EDR, NEF showed superior

cellular uptake and neuroprotective effect in SH-SY5Y695

APP cell line. Furthermore, it showed nontoxicity of NEF up to

414 µM/kg dose of EDR and its potential to reverse AD-like

behavior deficits of APP/PS1 mice in a dose-dependent

manner. The authors concluded that these findings indicated

that oral delivery of NEF holds promise as a safe and effective

therapeutic agent for AD.

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Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), commonly known as Lou

Gehrig’s disease, is a progressive, neurodegenerative disease

that destroys motor neurons. Patients with ALS gradually lose

their ability to control voluntary muscles that are involved in

breathing, chewing, talking, and walking; resulting in paralysis

and finally death. The Centers for Disease Control and

Prevention estimates that approximately 12,000 to 15,000

Americans have ALS; and the majority of patients with ALS die

from respiratory failure, usually within 3 to 5 years from when

the symptoms first commence. Riluzole is the only currently

approved mildly effective treatment; it received marketing

authorization in the U.S. in 1995 in the U.S. and in Europe in

1996. In the years that followed, over 60 molecules have been

investigated as a possible treatment for ALS. Despite

significant research efforts, the majority of clinical studies have

failed to demonstrate clinical effectiveness. In the past year,

oral masitinib and intravenous (IV) edaravone (a synthetic-free

radical scavenger) have emerged as promising new

therapeutic agent for the treatment of ALS (Petrov et al,

2017).

In a double-blind, parallel-group, placebo-controlled study, Abe

and colleagues (2014) examined the safety and effectiveness

of edaravone in patients with ALS. These researchers

conducted a 36-week clinical trial, consisting of 12-week pre

observation period followed by 24-week treatment period.

Patients received placebo (n = 104) or edaravone (n= 102) IV

infusion over 60 minutes for the first 14 days in cycle 1, and for

10 of the first 14 days during cycles 2 to 6. The efficacy

primary end-point was changes in the revised ALS functional

rating scale (ALSFRS-R) scores during the 24-week treatment

period. Changes in ALSFRS-R during the 24-week treatment

period were -6.35 ± 0.84 in the placebo group and -5.70 ± 0.85

in the edaravone group, with a difference of 0.65 ± 0.78 (p =

0.411). Adverse events (AEs) amounted to 88.5 % (92/104) in

the placebo group and 89.2 % (91/102) in the edaravone

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group. The authors concluded that the reduction of

ALSFRS-R was smaller in the edaravone group than in the

placebo group. Levels and frequencies of reported AEs were

similar in the 2 groups. These investigators stated that

although the elimination of free radicals by means of

edaravone to inhibit the degeneration of motor neurons

appeared to be a promising new strategy for the treatment of

ALS, this study did not demonstrate effectiveness of

edaravone in delaying the progression of ALS. They noted

that while the primary end-point was not attained, they

considered that these findings were helpful to identify the

patient population in which edaravone could be expected to

show effectiveness. On the basis of this information, these

researchers designed a phase-III clinical trial.

Noto and associates (2016) stated that therapies that inhibit

neuronal hyper-excitability may be effective in arresting the

progression of ALS. These investigators searched Medline

and ClinicalTrials.gov and selected randomized controlled

trials (RCTs) that covered neuro-protective therapy. Riluzole

has been established to reduce neuronal hyper-excitability.

More recently, initial studies of Na(+) channel blockers

(mexiletine and flecainide) have been investigated.

Separately, a trial of a K(+) channel activator (retigabine) is

underway, while edaravone is currently being considered for

licensing by drug approval agencies based on a hypothesis

that the elimination of free radicals may lead to protection of

motor neurons. The authors concluded that initial clinical trials

with Na(+) channel blockers have not yet established

effectiveness in ALS. Currently, retigabine is under evaluation

as a potential therapy; and edaravone has recently been

approved as a new therapeutic option for ALS in Japan.

Sawada (2017) noted that although the pathogenesis remains

unresolved, oxidative stress is known to play a pivotal role.

Edaravone works in the central nervous system as a potent

scavenger of oxygen radicals. In ALS mouse models,

edaravone suppresses motor functional decline and nitration

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http://ClinicalTrials.gov


of tyrosine residues in the cerebro-spinal fluid (CSF). These

investigators reviewed 3 clinical trials: 1 phase-II open-label

trial and 2 phase-III RCTs. In all trials, the primary outcome

measure was the changes in scores on the ALSFRS-R to

evaluate motor function of patients. The phase-II, open-label

trial suggested that edaravone is safe and effective in ALS,

markedly reducing 3-nitrotyrosine levels in the CSF. One of

the 2 RCTs showed beneficial effects in ALSFRS-R, although

the differences were not significant. The last trial

demonstrated that edaravone provided significant

effectiveness in ALSFRS-R scores over 24 weeks where

concomitant use of riluzole was permitted. Eligibility was

restricted to patients with a relatively short disease duration

and preserved vital capacity. Therefore, combination therapy

with edaravone and riluzole should be considered earlier.

Martinez and colleagues (2017) reviewed all the ALS ongoing

clinical trials (up to November 2016). They described them in

a comprehensive way and grouped them in the following

sections: biomarkers, biological therapies, cell therapy, drug

repurposing and new drugs. Despite multiple obstacles that

explain the absence of effective drugs for the treatment of

ALS, joint efforts among patient's associations, public and

private sectors have fueled innovative research in this field,

resulting in several compounds that are in the late stages of

clinical trials. The authors noted that edaravone was recently

approved in Japan and is pending in the U.S.

On May 5, 2017, the Food and Drug Administration (FDA)

approved edaravone (Radicava) for the treatment of patients

with ALS. The effectiveness of edaravone for the treatment of

ALS was demonstrated in a 6-month, randomized, placebo-

controlled, double-blind study conducted in Japanese patients

with ALS who were living independently and met the following

criteria at screening:

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▪ Functionality retained most activities of daily living

(defined as scores of 2 points or better on each

individual item of the ALS Functional Rating Scale –

Revised [ALSFRS-R; described below])

▪ Normal respiratory function (defined as percent-

predicted forced vital capacity values of [%FVC] greater

than or equal to 80 %)

▪ Definite or Probable ALS based on El Escorial revised

criteria

▪ Disease duration of 2 years or less.

The study enrolled 69 patients in the Radicava arm and 68 in

the placebo arm. Baseline characteristics were similar

between these groups, with over 90 % of patients in each

group being treated with riluzole. Radicava was administered

as an IV infusion of 60 mg given over a 60-minute period

according to the following schedule:

▪ An initial treatment cycle with daily dosing for 14 days,

followed by a 14-day drug-free period (Cycle 1)

▪ Subsequent treatment cycles with daily dosing for 10

days out of 14-day periods, followed by 14-day drug-free

periods (Cycles 2 to 6).

The primary efficacy end-point was a comparison of the

change between treatment arms in the ALSFRS-R total scores

from baseline to Week 24. The ALSFRS-R scale consists of

12 questions that evaluate the fine motor, gross motor, bulbar,

and respiratory function of patients with ALS (speech,

salivation, swallowing, handwriting, cutting food,

dressing/hygiene, turning in bed, walking, climbing stairs,

dyspnea, orthopnea, and respiratory insufficiency). Each item

is scored from 0 to 4, with higher scores representing greater

functional ability. The decline in ALSFRS-R scores from

baseline was significantly less in the Radicava-treated patients

as compared to placebo. The most common AEs reported by

subjects receiving edaravone were contusion and gait

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disturbance. Radicava is also associated with serious risks

that require immediate medical care, such as hives, swelling,

or shortness of breath, and allergic reactions to sodium

bisulfite, an ingredient in the drug. Sodium bisulfite may cause

anaphylactic symptoms that can be life-threatening in people

with sulfite sensitivity. The FDA granted Radicava orphan

drug designation, which provides incentives to assist and

encourage the development of drugs for rare diseases.

Mitsubishi Tanabe Pharma Corporation’s Package Insert on

“Radicut Injection” (2015) lists 3 clinical studies regarding the

use of edaravone injection for the treatment of ALS.

1st Confirmatory Study:

When edaravone or placebo was intravenously administered

at 60 mg in patients with ALS (warranting “Definite”, “Probable”

or “Probable-laboratory-supported” according to the El Escorial

and the revised Airlie House diagnostic criteria for ALS, rated

as grade 1 or 2 in Japan ALS severity classification, having %

FVC not less than 70 %, and illness duration within 3 years) in

6 cycles of treatment*1, mean changes from baseline in the

ALSFRS-R as primary end-point were not significantly different

between the edaravone-treated and placebo-treated groups

(-5.70 ± 0.85 versus -6.35 ± 0.84; p = 0.411).

2nd Confirmatory Study:


at 60 mg in patients with ALS (warranting “Definite” or

“Probable” according to the El Escorial and the revised Airlie

House diagnostic criteria for ALS, rated as grade 1 or 2 in

Japan ALS severity classification, having %FVC not less than

80 % and illness duration within 2 years) in 6 cycles of

treatment*1, there were significant differences in mean changes

from baseline in the ALSFRS-R as primary end-point between

the edaravone-treated and placebo-treated groups (-5.01 ±

0.64 versus -7.50 ± 0.66; p = 0.0013).

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A Placebo-Controlled Double-Blind Comparative Study in Patients with Japan ALS Severity Classification of Grade 3:


at 60 mg in patients with Japan ALS severity classification of

grade 3 ALS in 6 cycles of treatment*1, mean changes from

baseline in the ALSFRS-R as primary end-point were

significantly different between the edaravone-treated and

placebo-treated groups (-6.52 ± 1.78 versus -6.00 ± 1.83; p =

0.8347).

*1: Once-daily consecutive administration for 14 days and

subsequent cessation for 14 days of this product were

combined in the 1st cycle of treatment. After completion of the

1st cycle, this product was administered for 10 of 14 days

followed by cessation for 14 days from the 2nd to 6th cycle

(the treatment cycle was repeated 5 times).

Edaravone is also being investigated in the treatment of

various conditions/diseases (e.g., acute ischemic stroke,

choroidal neovascularization, intra-cerebral hemorrhage,

myocardial damage after ischemia and re-perfusion,

nephropathy, and osteoarthritis); however, its effectiveness for

these indications has not been established.

Asthma

Pan and colleagues (2020) noted that asthma is a chronic

disease that threatens public health worldwide. Multiple

studies have shown that oxidative stress plays an important

role in the pathogenesis of asthma. Edaravone has been

shown to have a protective effect against lung injury due to its

ability to eliminate reactive oxygen species. These

investigators examined the effect of EDR on asthma and the

mechanism underlying its actions. An experimental asthma

model was induced in mice, before they were treated with

different doses of EDR. Measurements of airway

responsiveness to methacholine (Mch), cell counts and

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cytokine levels in broncho-alveolar lavage fluid (BALF) and of

the oxidative products and antioxidant enzymes in lung tissue

were taken in these asthma model mice and compared with

control mice. Protein levels of kelch-like ECH-associated

protein-1 (Keap1)/nuclear factor erythroid 2-related factor 2

(Nrf2) and hemeoxygenase-1 (HO-1) were determined in the

lung tissue of normal mice and Nrf2 and HO-1-deficient mice

subject to the asthma model to examine the mechanisms

underlying EDR action. The results indicated that EDR

effectively reduced airway responsiveness to Mch. The total

number of cells and the numbers of eosinophils, lymphocytes

and neutrophils in BALF of asthma model mice were also

significantly reduced by EDR treatment when compared with

normal saline treatment. EDR treatment significantly alleviated

peri-vascular edema, peri-bronchial inflammation and

macrophage infiltration in the alveolar space and decreased

the levels of inflammatory cytokines released in BALF

compared with control. EDR also significantly reduced the

levels of oxidative stress markers in BALF and restored the

levels of antioxidative enzyme, superoxide dismutase, when

compared with control. The Keap1/Nrf2 ratio was significantly

decreased with EDR compared with control due to an increase

in Nrf2 and a decrease in Keap1 expression. HO-1 expression

was increased by EDR. The airway responsiveness of Nrf2-/

mice or HO-1-/- mice to Mch was significantly higher compared

with normal mice treated with EDR. The authors concluded

that the findings of the this study showed that EDR exerted anti-

inflammatory and antioxidative effects, which suggested a

potential use for EDR in reduction of asthma severity. The

activated Keap1/Nrf2 pathway and HO-1 may be involved in

the anti-asthmatic effect of EDR.

Autoimmune Thyroiditis

Li and co-workers (2018) noted that autoimmune thyroiditis is

among the most prevalent of all the auto-immunities in

population. It is characterized as both cellular immune

responses with T, B cells infiltrating to the thyroid gland

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followed by hypothyroidism as a result of destruction of the

thyroid follicles and fibrous replacement of the parenchymal

tissue, as well as immune response for TPO and Tg-antibody

production. Experimental autoimmune thyroiditis (EAT) has

been proven to be an ideal model to study autoimmune

thyroiditis. In the present study, these researchers induced an

EAT model in rats and examined the effect of edaravone on

EAT severity and explored the mechanism. The results

showed that edaravone reduced the severity score of

thyroiditis dose-dependently and the levels of serum TPOAb,

TgAb, T3 and T4. Edaravone significantly decreased the

mRNA level of IL-17, but increased the mRNA level of IL-10, IL

4, TNF-α and IFN-γ. EAT model significantly induced oxidative

stress, which was inhibited by the treatment of 10 mg/kg, 20

mg/kg or 40 mg/kg of edaravone. The EAT model

significantly increased the Akt and STAT3 phosphorylation, but

when rats were treated with 20 mg/kg or 40 mg/kg edaravone,

they were significantly inhibited. The HO-1 expression was

greatly increased by 20 mg/kg or 40 mg/kg edaravone. The

PI3K inhibitor LY294002, Akt inhibitor triciribine or STAT3

inhibitor WP1066 all significantly decreased the severity score

of thyroiditis in the EAT model group, while the HO-1 inhibitor

ZnPP-IX increased the severity score of thyroiditis. The

authors concluded that these findings confirmed the

involvement of ROS and HO-1-dependent STAT3/PI3K/Akt

pathway in the process of Hashimoto's thyroiditis and

suggested the potential usage of edaravone in the therapy of

it.

Brain Radionecrosis

Chung and colleagues (2018) stated that brain radionecrosis

can occur following high-dose radiotherapy to brain tissue and

can have a significant impact on a person's quality of life

(QOL) and function. The underlying pathophysiological

mechanism remains unclear for this condition, which makes

establishing effective treatments challenging. In a Cochrane

review, these investigators evaluated the effectiveness of

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interventions used for the treatment of brain radionecrosis in

adults over 18 years old. In October 2017, these researchers

searched the Cochrane Register of Controlled Trials

(CENTRAL), Medline, Embase and the Cumulative Index to

Nursing and Allied Health Literature (CINAHL) for eligible

studies. They also searched unpublished data through

Physicians Data Query, www.controlled-trials.com/rct,

www.clinicaltrials.gov, and www.cancer.gov/clinicaltrials for

ongoing trials and hand-searched relevant conference

material. These investigators included RCTs of any

intervention directed to treat brain radionecrosis in adults over

18 years old previously treated with radiation therapy to the

brain. These investigators anticipated a limited number of

RCTs, so they also planned to include all comparative

prospective intervention trials and quasi-randomized trials of

interventions for brain radionecrosis in adults as long as these

studies had a comparison group that reflects the standard of

care (i.e., placebo or corticosteroids). Selection bias was likely

to be an issue in all the included non-randomized studies

therefore results were interpreted with caution. Two review

authors independently extracted data from selected studies

and completed a “risk of bias” assessment. For dichotomous

outcomes, the odds ratio (OR) for the outcome of interest was

reported. For continuous outcomes, treatment effect was

reported as MD between treatment arms with 95 % CIs. Two

RCTs and 1 prospective non-randomized study evaluating

pharmacological interventions met the inclusion criteria for this

review. As each study evaluated a different drug or

intervention using different end-points, a meta-analysis was

not possible. There were no trials of non-pharmacological

interventions that met the inclusion criteria. A very small

randomized, double-blind, placebo-controlled trial of

bevacizumab versus placebo reported that 100 % (7/7) of

participants on bevacizumab had reduction in brain edema by

at least 25 % and reduction in post-gadolinium enhancement,

whereas all those receiving placebo had clinical or radiological

worsening or both. This was an encouraging finding but due

to the small sample size these researchers did not report a

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http://www.controlled-trials.com/rct

http://www.clinicaltrials.gov/

http://www.cancer.gov/clinicaltrials


relative effect. The authors also failed to provide adequate

details regarding the randomization and blinding procedures.

Therefore, the certainty of this evidence was low and a larger

RCT adhering to reporting standards is needed. An open-

label RCT demonstrated a greater reduction in brain edema

(T2 hyper-intensity) in the edaravone plus corticosteroid group

than in the corticosteroid alone group (MD was 3.03 (95 % CI:

0.14 to 5.92; low-certainty evidence due to high risk of bias

and imprecision); although the result approached borderline

significance, there was no evidence of any important

difference in the reduction in post-gadolinium enhancement

between arms (MD = 0.47, 95 % CI: - 0.80 to 1.74; low-

certainty evidence due to high risk of bias and imprecision). In

the RCT of bevacizumab versus placebo, all 7 participants

receiving bevacizumab were reported to have neurological

improvement, whereas 5 of 7 participants on placebo had

neurological worsening (very low-certainty evidence due to

small sample size and concerns over validity of analyses).

While no AEs were noted with placebo, 3 severe AEs were

noted with bevacizumab, which included aspiration

pneumonia, pulmonary embolus and superior sagittal sinus

thrombosis. In the RCT of corticosteroids with or without

edaravone, the participants who received the combination

treatment were noted to have significantly greater clinical

improvement than corticosteroids alone based on

LENT/SOMA scale (OR = 2.51, 95 % CI: 1.26 to 5.01; low-

certainty evidence due to open-label design). No differences

in treatment toxicities were observed between arms. One

included prospective non-randomized study of alpha

tocopherol (vitamin E) versus no active treatment was found

but it did not include any radiological assessment. As only 1

included study was a double-blinded RCT, the other studies

were prone to selection and detection biases. None of the

included studies reported QOL outcomes or adequately

reported details about corticosteroid requirements. A limited

number of prospective studies were identified but

subsequently excluded as these studies had a limited number

of participants evaluating different pharmacological

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interventions using variable end-points. The authors

concluded that there is a lack of good certainty evidence to

help quantify the risks and benefits of interventions for the

treatment of brain radionecrosis after radiotherapy or

radiosurgery. In an RCT of 14 patients, bevacizumab showed

radiological response that was associated with minimal

improvement in cognition or symptom severity. Although it

was a randomized trial by design, the small sample size limited

the quality of data. A trial of edaravone plus corticosteroids

versus corticosteroids alone reported greater reduction in the

surrounding edema with combination treatment but no effect

on the enhancing radionecrosis lesion. Due to the open-label

design and wide CIs in the results, the quality of this data was

also low. There was no evidence to support any non-

pharmacological interventions for the treatment of

radionecrosis. They stated that further prospective

randomized studies of pharmacological and non-

pharmacological interventions are needed to generate

stronger evidence; 2 ongoing RCTs, 1 evaluating

bevacizumab and 1 evaluating hyperbaric oxygen therapy

were identified.

Choroidal Neovascularization

Masuda and colleagues (2016) stated that choroidal neo

vascularization (CNV) is a main characteristic in exudative

type of age-related macular degeneration. These researchers

examined the effects of edaravone on laser-induced CNV,

which was induced by laser photocoagulation to the subretinal

choroidal area of mice and common marmosets. Edaravone

was administered either intra-peritoneally (IP) twice-daily for 2

weeks or intravenously just once after laser photocoagulation.

The effects of edaravone on laser-induced CNV were

evaluated by fundus fluorescein angiography, CNV area

measurements, and the expression of 4-hydroxy-2-nonenal

(4-HNE) modified proteins, a marker of oxidative stress.

Furthermore, the effects of edaravone on the production of

hydrogen peroxide (H2O2)-induced reactive oxygen species

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(ROS) and vascular endothelial growth factor (VEGF)-induced

cell proliferation were evaluated using human retinal pigment

epithelium cells (ARPE-19) and human retinal microvascular

endothelial cells, respectively. Choroidal neo-vascularization

areas in the edaravone-treated group were significantly

smaller in mice and common marmosets. The expression of 4

HNE modified proteins was up-regulated 3 hours after laser

photocoagulation, and intravenously administered edaravone

decreased it. In in-vitro studies, edaravone inhibited H2O2

induced ROS production and VEGF-induced cell proliferation.

The authors concluded that these findings suggested that

edaravone may protect against laser-induced CNV by

inhibiting oxidative stress and endothelial cell proliferation.

Cisplatin-Induced Chronic Renal Injury

Koike and colleagues (2019) noted that cisplatin has been

widely used as an anti-cancer agent for a wide range of

tumors, however, it had nephrotoxicity that was mainly caused

by oxidative stress. Edaravone has reportedly been validated

to have a protective effect against renal injury induced by

reactive oxygen species. However, most of these reports were

against AKI, and few studies have examined the effect of

chronic renal injury. These investigators examined the effect

of edaravone on cisplatin nephropathy in the chronic phase. A

total of 25 male Wistar rats were divided into 5 groups: control,

cisplatin, cisplatin + edaravone 1 mg kg-1, cisplatin + edaravone

10 mg kg-1, and cisplatin + edaravone 100 mg kg-1.

Edaravone was administrated intra-peritoneally every other

day for 5 weeks, starting 1 week before cisplatin administration

(6 mg kg-1, i.p.). As a result, proximal tubule injury, interstitial

fibrosis, and mononuclear cell infiltration were ameliorated

histologically in the group of rats treated with high edaravone

dose. In the cisplatin group, the number of α-SMA-, CD68-,

and CD3-positive cells increased markedly compared with the

control group, but these numbers were significantly decreased

by higher doses of co-administered edaravone. The authors

concluded that while there was no clear mRNA expression

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variation in antioxidant enzymes, the apoptosis-promoting

factors, caspase8, were markedly reduced in the high-dose

edaravone co-administration group compared with the cisplatin

group. These researchers stated that these findings

suggested that cisplatin-induced renal injury in the chronic

phase was ameliorated by edaravone.

Doxorubicin-Induced Cardiotoxicity / Nephrotoxicity

Hassan and associates (2019) stated that doxorubicin (DOX)

is a potential chemotherapeutic agent but its use is restricted

due to cardiotoxicity. Edaravone is a potent-free radical

scavenging agent used in cerebral ischemia. Benidipine is a

triple calcium channel blocker (CCB). These investigators

examined the potential cardio-protective effects of EDR and

benidipine alone and their combination against DOX-induced

cardiotoxicity. Cardiotoxicity was induced by administering 6

equal injections of DOX (2.5 mg/kg) on alternative days for 2

weeks. DOX-treated group showed significant increase level

of lipid peroxide and decrease in antioxidant status along with

mitochondrial enzymatic activity. Cardiotoxic effect of DOX

illustrated by significantly increased the cardiac biomarkers

such as cardiac troponin-I, brain natriuretic peptide (BNP),

creatine kinase-MB in serum. Significant increased activation

of TNF-α, caspase-3 activity and myocardial infarct (MI) size in

DOX-treated group. Histopathological evaluation also

confirmed the DOX-induced cardiotoxicity. Pre-treated with

EDR and benidipine significantly attenuated level of

thiobarbituric acid reactive substance, endogenous enzymes,

mitochondrial enzyme activities and cardiac biomarkers.

Furthermore, pre-treated group showed decreased activation

of TNF-α, caspase-3 activity along with reduction in the MI

size. Histopathological evaluation also strengthened the

above results. The authors concluded that these findings

suggested that the pre-treatment with EDR and benidipine

have potential protective effect against DOX-induced

cardiotoxicity.

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Demir and colleagues (2020) examined the nephroprotective

effect of EDR on DOX-induced nephrotoxicity. A total of 28

Wistar male rats were used; they were separated into 4 groups

(n = 7 for each group). Group І (control) rats were treated with

saline (4 ml/kg); in group ІІ (DOX), nephrotoxicity was induced

by 3 doses of 18 mg/kg/i.p. DOX, at a 24-hour interval on the

12th, 13th, and 14th days; in group ІІІ (EDR), rats were treated

with EDR (30 mg/kg/for 14 days), and in group ІV (EDR +

DOX), rats were treated with EDR (30 mg/kg/for 14 days) and

DOX were injected (18 mg/kg/for 3 days; at a 24-hour interval

on the 12th, 13th, and 14th days). On the 15th day of the

experiment, technetium-99m-labeled dimercaptosuccinic acid

([99mTc]DMSA) uptake was obtained in both kidneys and

biochemical parameters from serum and kidney tissue were

measured. DOX led to nephrotoxicity through elevation of

serum BUN, creatinine and TNF-α, NO, and IL-6 in kidney

tissue and decreased [99mTc]DMSA uptake level in the kidney

when compared with control group (p < 0.01). The authors

concluded that pre-treatment EDR significantly decreased

BUN and creatinine, also kidney tissue TNF-α, IL-6, NO, and

increased [99mTc]DMSA uptake level compared with the

DOX; EDR had a significant nephron-protective effect through

the attenuation of oxidative stress and inflammatory markers

during DOX-induced nephrotoxicity in rats.

Multiple Sclerosis

Agresti and colleagues (2019) stated that multiple sclerosis

(MS) is a chronic inflammatory disease of the central nervous

system (CNS) leading to demyelination and

neurodegeneration, with a complex and still to be clarified

etiology. Data coming from patients' samples and from animal

models showed that oxidative status (OS) plays an important

role in MS pathogenesis. Over-production of reactive

oxidative species by macrophages/microglia could bring about

cellular injury and ensuing cell death by oxidizing cardinal

cellular components. Oxidized molecules are present in active

MS lesions and are associated with neurodegeneration.

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These researchers undertook a structured search of

bibliographic databases for peer-reviewed research literature

focusing on OS in MS. The contents of the selected papers

were described in the context of a conceptual framework. A

special emphasis was given to the results of the authors’ study

in the field. The results of their 3 recent studies were put in the

context and discussed taking into account the literature on the

topic. Oxidative damage underpinned an imbalance shared by

MS and neurodegenerative diseases such as AD and PD. In

people with clinically isolated syndrome (an early phase of MS)

oxidative stress proved to contribute to disease

pathophysiology and to provide biomarkers that may help

predict disease evolution. A drug screening platform based on

multiple assays to test the re-myelinating potential of library of

approved compounds showed 2 anti-oxidants, edaravone and 5

methyl-7-methoxyisoflavone, as active drugs. Moreover, an

analysis of “structure activity relationship” showed off-targets

sites of these compounds that accounted for their re

myelinating activity, irrespective of their antioxidant action.

The authors concluded that edaravone emerged as a

candidate to treat complex disease such as MS, where

inflammation, oxidative stress and neurodegeneration

contribute to disease progression, together or individually, in

different phases and disease types. Furthermore, approaches

based on drug re-positioning appeared to maintain the

promise of helping discover novel treatment for complex

diseases, where molecular targets are largely unknown.

Myocardial Damage After Ischemia and Re-Perfusion

Zheng and associates (2015) evaluated the safety and

effectiveness of edaravone for myocardial damage during

myocardial ischemia and reperfusion (I/R). These researchers

included RCTs that compared edaravone with placebo or no

intervention in patients with acute myocardial infarction (MI) or

undergoing coronary artery bypass. Two authors selected

eligible trials, assessed trial quality and independently

extracted the data. A total of 7 clinical trials were eventually

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included and analyzed in this study, involving 148 participants;

4 trials were defined as waiting assessment. All of the 3

remaining trials compared edaravone and another treatment

combined with other treatment alone, used the same dose of

edaravone injections (60 mg/day) and course of treatment (14

days), evaluated the effect of edaravone at different times,

applied different methods, reported AEs, and showed no

differences between the treatment group and the control

group. When pooling all of the trials in 1 dataset, edaravone

appeared to decrease the proportion of participant with

marked myocardial damage during I/R as compared with the

control group. The meta-analysis also revealed decreased

cardiac markers such as creatine kinase myocardial b fraction

(CK-MB), cardiac troponin I (cTnI) and erythrocyte membrane

malonyldialdehyde (MDA), and increased content of

superoxide dismutase (SOD). The authors concluded that as

a consequence of the moderate risk of bias and small sample,

the observation of an effective treatment trend of edaravone

for I/R requires future larger, high-quality trials to confirm.

Nephropathy

Varatharajan and colleagues (2016) stated that edaravone has

been reported to reduce ischemia-reperfusion-induced renal

injury by improving tubular cell function, and lowering serum

creatinine (Cr) and renal vascular resistance. These

researchers examined the effect of edaravone in diabetes

mellitus-induced nephropathy in rats. A single administration

of streptozotocin (STZ, 55 mg/kg, IP) was employed to induce

diabetes mellitus in rats. The STZ-administered diabetic rats

were allowed for 10 weeks to develop nephropathy. Mean

body weight, lipid alteration, renal functional and

histopathology were analyzed. Diabetic rats developed

nephropathy as evidenced by a significant increase in serum

Cr and urea, and marked renal histopathological abnormalities

like glomerulo-sclerosis and tubular cell degeneration. The

kidney weight to body weight ratio was increased. Moreover,

diabetic rats showed lipid alteration as evidenced by a

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significant increase in serum triglycerides and decrease in

serum high-density lipoproteins (HDLs). Edaravone (10

mg/kg, IP, last 4-weeks) treatment markedly prevented the

development of nephropathy in diabetic rats by reducing

serum Cr and urea and preventing renal structural

abnormalities. In addition, this treatment, without significantly

altering the elevated glucose level in diabetic rats, prevented

diabetes mellitus-induced lipid alteration by reducing serum

triglycerides and increasing serum HDLs. Interestingly, the

reno-protective effect of edaravone was comparable to that of

lisinopril (5 mg/kg, P.O. 4 weeks, standard drug). The authors

concluded that edaravone prevented renal structural and

functional abnormalities and lipid alteration associated with

experimental diabetes mellitus; it has the potential to prevent

nephropathy without showing an anti-diabetic action,

implicating its direct reno-protection in diabetic rats.

Osteoarthritis

Huang and colleagues (2016) stated that osteoarthritis (OA) is

a degenerative joint disease affecting millions of people. The

degradation and loss of type II collagen induced by pro-

inflammatory cytokines secreted by chondrocytes, such as

tumor necrosis factor-alpha (TNF-α) is an important

pathological mechanism to the progression of OA. Whether

edaravone has a protective effect in articular cartilage has not

been reported. These researchers examined the chondrocyte

protective effects of edaravone on TNF-α induced degradation

of type II collagen, and found that TNF-α treatment resulted in

degradation of type II collagen, which can be ameliorated by

treatment with edaravone in a dose-dependent manner. It

was found that the inhibitory effects of edaravone on TNF-α

induced reduction of type II collagen were mediated by matrix

metalloproteinase 3 (MMP-3) and MMP-13. The authors

concluded that edaravone alleviated TNF-α induced activation

of signal transducer and activator of transcription 1 (STAT1)

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and expression of interferon regulatory factor 1 (IRF-1); these

findings suggested a potential protective effect of edaravone in

OA.

Parkinson Disease

Karba and colleagues (2018) noted that Parkinson's disease

(PD) is one of the most common neurodegenerative disorder

with intricate progressive pathology. Currently, available

conventional options for PD have certain limitations of their

own, and as a result, patient compliance and satisfaction are

low. Current therapeutic options provide only symptomatic

relief with limited control to prevent disease progression,

resulting in poor patient compliance and satisfaction. Several

emerging pharmacotherapies for PD are in different stages of

clinical development. These therapies include adenosine A2A

receptor antagonists, glutamate receptor antagonists,

monoamine oxidase inhibitors, anti-apoptotic agents, and

antioxidants such as coenzyme Q10, N-acetyl cysteine, and

edaravone. Other emerging non-pharmacotherapies include

viral vector gene therapy, microRNAs, transglutaminases,

RTP801, stem cells and glial-derived neurotrophic factor

(GDNF). In addition, surgical procedures including deep brain

stimulation, pallidotomy, thalamotomy and Gamma Knife

surgery have emerged as alternative interventions for

advanced PD patients who have completely utilized standard

treatments and still suffer from persistent motor fluctuations.

Complementary and alternative medicine (CAM) modalities

such as Yoga, acupuncture, Tai Chi, music therapies etc. are

highly practiced in several countries, offer some of the safer

and effective treatment modalities for PD. While several of

these therapies hold much promise in delaying the onset of the

disease and slowing its progression, more pharmacotherapies

and surgical interventions need to be investigated in different

stages of PD. It is hoped that these emerging therapies and

surgical procedures will strengthen our clinical armamentarium

for improved treatment of PD.

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Post-Stroke Depression

Kong and colleagues (2020) examined the effect of EDR on

depression relief in symptomatic patients with intra-cranial

stenosis and its relationship with the expression of sex

hormones. These investigators recruited 112 patients with

symptomatic intra-cranial arterial stenosis from Renmin

Hospital, Wuhan University, between October 2014 and

October 2017. All patients were divided into the traditional or

experimental (traditional treatment + intravenous infusion of

EDR 30 mg twice-daily for 14 days) treatment groups. The

general clinical data were collected, and neurological

functional recovery using the mRS and NIHSS scores were

recorded. Symptom Checklist 90 (SCL-90) was used to

assess the general psychological changes of the patient,

followed by the 24 Hamilton Depression Scale (HAMD) to

examine the incidence of post-stroke depression (PSD). This

divided the patients into the mild, moderate, and severe

depression groups. These researchers also measured the

serum protein expression of the sex hormones estradiol (E2),

testosterone (T), follicle stimulating hormone (FSH), prolactin

(PRL), and luteinizing hormone (LH). The mRS and NIHSS

scores were significantly lower in the experimental group than

in the control group (p <0.05). There was no significant

difference in SCL90 score before intervention (p >0.05); the

scores were significantly lower in the experimental group after

intervention (p <0.05)> There was a significant difference in

SCL-90 and HAMD scores between groups before treatment

(p <0.05), with significantly lower scores in the experimental

group post-treatment (p <0.05). The incidence of depression

was significantly reduced in the experimental group post-

treatment. Furthermore, the expression of E2 and FSH was

significantly higher (p <0.01) and lower (p < 0.001),

respectively, in women than in men in the experimental group

post-treatment. Interestingly, the expression of T was

significantly lower in men in the experimental group post-

treatment (p <0.001). The authors concluded that EDR

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significantly improved the clinical efficacy of stent implantation

in intra-cranial artery stenosis treatment by alleviating

depression and reducing the incidence of PSD.

The authors stated that there were some drawbacks in this

study, such as the lack of long-term continuity, further clinical

follow-up, and prospective clinical data. In this trial, these

investigators collected clinical data from patients at 7 days and

4 weeks post-treatment. Further prospective studies will be

carried out to collect clinical data at baseline, and 3, 6, 12, and

24 months after intervention to further evaluate the clinical

efficacy of EDR and its relationship with the sex hormones. In

addition, the study lacked further clinical follow-up data, such

as sub-group analyses of the specific infarct location, degree

of arterial stenosis, and location of the symptomatic intra-

cranial arterial stenosis. Finally, there was a lack of

prospective clinical data.

Rheumatoid Arthritis

Zhang and colleagues (2020) stated that current research

suggests that synovial phagocytic cells remove excessive

amounts of free oxygen radicals (reactive oxygen species

[ROS]), thereby preventing damage to synovial tissues.

Moreover, ROS may affect the expression of growth arrest

and DNA damage inducible α (GADD45A), thus further

promoting the activation of synovial fibroblasts. In this study,

male adult rats were examined for progression of collagen-

induced arthritis (CIA) using a macroscopic arthritis scoring

system of the hind-paws and by measuring the changes in the

rat's body weight, and activity level before and after diagnosis

of CIA. Rats were intraperitoneally injected twice-daily with

EDR at doses of 3, 6, and 9 ml/kg. Samples were taken at 2,

4, and 6 weeks, respectively. EDR was found to significantly

reduce macroscopic arthritis and microscopic pathology scores

in CIA rats. The concentration of endothelial NOS-6,

glutathione, and heme oxygenase-1 in the serum of rats

decreased, as was the production of ROS around the

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synovium and inflammatory factors. Moreover, ROS-1

increased the expression of the NF-κB p65 protein by altering

the expression level of GADD45A, causing aggravation of

tissue damage. EDR also significantly improved the

physiological condition of CIA rats, including appetite, weight

changes, and loss of fur, as well as limb mobility. The authors

believed that EDR acted to reduce the expression of NF-ĸB

p65 by clearing ROS, which causes reduced expression of

GADD45A, and subsequently reduced the level of apoptosis

and inflammatory response proteins, thus, reducing the

symptoms of CIA. These researchers proposed that EDR is

an effective option for clinical treatment of rheumatoid arthritis.

Seizure

Hao and colleagues (2020) stated that previous studies have

demonstrated that excessive free radicals play an essential

role in the initiation and progression of epilepsy and that a

novel exogenous free radical scavenger EDR exerts some

neuroprotective effects on seizure-induced neuronal damage.

These researchers examined the possible molecular

mechanisms of EDR associated with procaspase-3

denitrosylation and activation through the FasL-Trx2 pathway

in seizures rats. They examined the effects of EDR on the

regulation of the combination of Fas ligand/Fas receptor and

the major components of the death-inducing signaling complex

(DISC) in the hippocampus of kainic acid (KA)-treated Sprague-

Dawley (SD) rats. Treatment with EDR could attenuate the

increased expression of FasL induced by KA and prevent

procaspase-3 denitrosylation and activation via suppression of

the FasL-Trx2 signaling pathway, which alleviated the neuronal

damage in seizures. The authors concluded that these findings

provided experimental evidence that EDR functions by

preventing the denitrosylation and activation of procaspase-3

and that EDR acts as a therapeutic option for epilepsy.

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Subarachnoid Hemorrhage

Cai and colleagues (2020) examined the effects of EDR

combined with cinepazide maleate on neurocyte autophagy

and neurological function in rats with subarachnoid

hemorrhage (SAH). A total of 80 Sprague Dawley rats were

selected to establish SAH rat models, which were divided into

sham operation group, SAH group, MCI group and combined

group. Hippocampal tissue of each group was taken to

observe the number of neurocytes. The expression levels of

Beclin-1 and (light chain LC3)-II of rats in each group were

detected by ELISA. Pearson's correlation factors were used to

analyze the correlation between Beclin-1 and LC3-11, and

neurological function tests were performed on rats of each

group 14 and 28 days after administration. The morphological

and structural damage of nerve cells in the combined group

was further alleviated, and the survival rate of neurons

significantly increased at all time-points (p < 0.05). The

expression levels of Beclin-1 and LC3-11 in combined group

was significantly higher than those in SAH group and CMI

group (p < 0.05), and Beclin-1 was positively correlated with

LC3-11 (r = 0.9454). Longa score of the combined group was

significantly lower than that of the other 2 groups, and muscle

strength score was significantly higher than that of the other 2

groups (p < 0.05). The authors concluded that EDR combined

with cinepazide maleate could enhance the survival rate of

brain cells and promote the volatilization of neurological

function in the treatment of hemorrhage in the subretinal space

of the omentum, which is worthy of popularization and

application.

Traumatic Brain Injury

Zhang and colleagues (2019) stated that traumatic brain injury

(TBI) is among the leading causes of irreversible neurological

damage and death worldwide. These investigators examined

if edaravone (EDA) had a neuroprotective effect on TBI and

identified the potential mechanism. Results demonstrated that

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EDA suppressed inflammatory and oxidative responses in

mice following TBI. This was evidenced by a reduction in

glutathione peroxidase, interleukin 6 (IL-6), tumor necrosis

factor-alpha (TNF-α) and hydrogen peroxide levels, in addition

to an increase in hemeoxygenase-1, quinone oxidoreductase

1 and superoxide dismutase levels, thus mitigating

neurofunctional deficits, cell apoptosis and structural damage.

These researchers found that EDA prevented the transfer of

NF-κB protein from the cytoplasm to the nucleus, while

promoting the expression of nuclear factor erythroid 2-related

factor 2 (Nrf2) protein in mice following TBI. The authors

concluded that these findings indicated that EDA exerted

neuroprotective effects, including impeding neurofunctional

deficits, cell apoptosis and structural damage, in mice with TBI,

potentially via suppression of NF-κB-mediated inflammatory

activation and promotion of the Nrf2 antioxidant pathway.

These researchers stated that these findings provided

evidence for the potential clinical application of EDA in the

treatment of TBI.

Wound Healing

Tamer and colleagues (2018) noted that a novel wound

healing material composed of chitosan (Ch) and hyaluronan

(HA) boosted with edaravone (Ed) as an anti-inflammatory

drug was developed. The fabricated membranes were verified

using FT-IR, and the thermal properties were estimated

employing TGA instrument. Moreover, physical

characterizations of the prepared membranes demonstrated a

decrease in the membrane wettability, whereas an increase in

membrane roughness was monitored due to the effect of

edaravone supplementation. A comparative study of free-

radical scavenging activity of edaravone itself was carried out

by 2 in-vitro approaches: uninhibited/inhibited hyaluronan

degradation and de-colorization of ABTS methods in normal

and simulated inflammation condition (acidic condition).

Accordingly, the scavenging activity of edaravone was

significantly diminished to OH and peroxy-/alkoxy-type radicals

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in acidic conditions in compared to the neutral reactions. The

biochemical studies evidenced the hemo-compatibility of the

examined membranes. The consequence of membranes

composed of Ch/HA/Ed on the wound healing of the rat's skin

was studied, and the macroscopic and microscopic

investigations revealed remarkable healing at 21st day post-

surgery compared with injuries treated with cotton gauze as a

negative control in addition to Ch/HA membrane without

edaravone. For these reasons, the Ch/HA/Ed membrane

could be implemented as wound dressing material.

Appendix

ALS Functional Rating Scale-Revised [ALSFRS-R]

The ALSFRS-R scale consists of 12 questions that evaluate

the fine motor, gross motor, bulbar, and respiratory function of

patients with ALS (speech, salivation, swallowing, handwriting,

cutting food, dressing/hygiene, turning in bed, walking,

climbing stairs, dyspnea, orthopnea, and respiratory

insufficiency). Each item is scored from 0 to 4, with higher

scores representing greater functional ability.

ALSFRS-R Scale and Calculator (http://www.outcomes

umassmed.org/ALS/alsscale.aspx)

Revised El Escorial Schema for the Clinical Diagnosis of ALS

The body is divided into 4 regions: (i) cranial, (ii) cervical, (iii)

thoracic and (iv) lumbosacral.

▪ Clinically Definite ALS: Defined on clinical evidence alone

by the presence of UMN, as well as LMN signs, in 3

regions.

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http://www.outcomes-umassmed.org/ALS/alsscale.aspx

http://www.outcomes-umassmed.org/ALS/alsscale.aspx


▪ Clinically Probable ALS: Defined on clinical evidence

alone by UMN and LMN signs in at least 2 regions with

some UMN signs necessarily rostral to (above) the LMN

signs.

▪ Clinically Probable-Laboratory-Supported ALS: Defined

when clinical signs of UMN and LMN dysfunction are in

only 1 region, or when UMN signs alone are present in 1

region, and LMN signs defined by EMG criteria are

present in at least 2 limbs, with proper application of

neuroimaging and clinical laboratory protocols to

exclude other causes.

▪ Clinically Possible ALS: Defined when clinical signs of

UMN and LMN dysfunction are found together in only 1

region or UMN signs are found alone in 2 or more

regions; or LMN signs are found rostral to UMN signs

and the diagnosis of Clinically Probable-Laboratory-

Supported ALS cannot be proven by evidence on clinical

grounds in conjunction with electrodiagnostic,

neurophysiologic, neuroimaging or clinical laboratory

studies. Other diagnoses must have been excluded to

accept a diagnosis of Clinically Possible ALS.

▪ Clinically Suspected ALS: Defined as a pure LMN

syndrome, wherein the diagnosis of ALS could not be

regarded as sufficiently certain to include the patient in

a research study.

LMN: lower motor neuron sign(s); UMN: upper motor neuron

sign(s).

Source: Elman LB, McCluskey L. Diagnosis of amyotrophic

lateral sclerosis and other forms of motor neuron disease.

UpToDate Inc., April 2017.

CPT Codes / HCPCS Codes / ICD-10 Codes

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Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":

Code Code Description

Other CPT codes related to the CPB:

96365 Intravenous infusion, for therapy, prophylaxis,

or diagnosis(specify substance or drug); initial,

up to 1 hour

HCPCS codes covered if selection criteria are met:

J1301 Injection, edaravone, 1 mg

ICD-10 codes covered if selection criteria are met:

G12.21 Amyotrophic lateral sclerosis

ICD-10 codes not covered for indications listed in the CPB:

E06.3 Autoimmune thyroiditis

F06.31 Mood disorder due to known physiological

condition with depressive features

G20 Parkinson's disease

G30.0 -

G30.9

Alzheimer's disease

G35 Multiple sclerosis

G40.001 -

G40.919

Epilepsy and recurrent seizures

G93.40 Encephalopathy, unspecified

H31.8 Other specified disorders of choroid [choroidal

neovascularization]

I25.5 Ischemic cardiomyopathy [myocardial damage

after ischemia and re-perfusion]

I60.00 -

I60.9

Nontraumatic subarachnoid hemorrhage

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I61.0 -

I61.9

Nontraumatic intracerebral hemorrhage

I63.00 -

I63.9

Cerebral infarction

I69.398 Other sequelae of cerebral infarction

J45.20 -

J45.998

Asthma

K85.00 -

K85.92

Acute pancreatitis

M05.00 -

M06.9

Rheumatoid arthritis

M15.0 -

M19.93

Osteoarthritis

N00.0 -

N08

Glomerular diseases [nephropathy]

N10 -

N16

Renal tubulo-interstitial diseases [nephropathy]

N14.1 Nephropathy induced by other drugs,

medicaments and biological substances

[cisplatin-induced chronic renal injury]

[doxorubicin-induced nephrotoxicity]

N17.0 -

N19

Acute kidney failure and chronic kidney disease

[nephropathy]

N25.0 -

N29

Other disorders of kidney and ureter

[nephropathy]

R56.00 -

R56.9

Convulsions, not elsewhere classified

Numerous

Options

Wound healing

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S06.340A

-

S06.369S

Traumatic hemorrhage of cerebrum

S06.9x0A

-

S06.9x9S

TBI (traumatic brain injury)

S27.301A

-

S27.399S

Other and unspecified injuries of lung

S36.200A

-

S36.299S

Injury of pancreas

S36.500A

-

S36.599S

Injury of colon

T46.991A

-

T46.996S

Poisoning by, adverse effect of and

underdosing of other agents primarily affecting

the cardiovascular system [doxorubicin-induced

cardiotoxicity]

T66.xxxA

-

T66.xxxS

Radiation sickness [brain radionecrosis]

The above policy is based on the following references:

1. Abe K, Itoyama Y, Sobue G, et al; Edaravone ALS Study

Group. Confirmatory double-blind, parallel-group,

placebo-controlled study of efficacy and safety of

edaravone (MCI-186) in amyotrophic lateral sclerosis

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patients. Amyotroph Lateral Scler Frontotemporal

Degener. 2014;15(7-8):610-617.

2. Agresti C, Mechelli R, Olla S, et al. Oxidative status in

multiple sclerosis and off-targets of antioxidants: The

case of edaravone. Curr Med Chem. 2019 Jan 24 [Epub

ahead of print].

3. Bao Q, Hu P, Xu Y, et al. Simultaneous blood-brain

barrier crossing and protection for stroke treatment

based on edaravone-loaded ceria nanoparticles. ACS

Nano. 2018;12(7):6794-6805.

4. Cai Z, Zhang H, Song H, et al. Edaravone combined

with cinepazide maleate on neurocyte autophagy and

neurological function in rats with subarachnoid

hemorrhage. Exp Ther Med. 2020;19(1):646-650.

5. Chiriboga CA. Acute toxic-metabolic encephalopathy in

children. UpToDate [online serial]. Waltham, MA:

UpToDate; reviewed August 2019.

6. Chung C, Bryant A, Brown PD. Interventions for the

treatment of brain radionecrosis after radiotherapy or

radiosurgery. Cochrane Database Syst Rev.

2018;7:CD011492.

7. Demir F, Demir M, Aygun H. Evaluation of the

protective effect of edaravone on doxorubicin

nephrotoxicity by [99mTc]DMSA renal scintigraphy

and biochemical methods. Naunyn Schmiedebergs

Arch Pharmacol. 2020 Feb 8 [Epub ahead of print].

8. EFNS Task Force on Diagnosis and Management of

Amyotrophic Lateral Sclerosis: Andersen PM,

Abrahams S, Borasio GD, et al. EFNS guidelines on the

clinical management of amyotrophic lateral sclerosis

(MALS) -- revised report of an EFNS task force. Eur J

Neurol. 2012;19(3):360-375.

9. Fu ZY, Wu ZJ, Zheng JH, et al. Edaravone ameliorates

renal warm ischemia-reperfusion injury by

downregulating endoplasmic reticulum stress in a rat

resuscitation model. Drug Des Devel Ther.

2020;14:175-183.

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10. Hao L, Dong L, Yu Q, et al. Edaravone inhibits

procaspase-3 denitrosylation and activation through

FasL-Trx2 pathway in KA-induced seizure. Fundam Clin

Pharmacol. 2020 Mar 25 [Epub ahead of print].

11. Hassan MQ, Akhtar MS, Afzal O, et al. Edaravone and

benidipine protect myocardial damage by regulating

mitochondrial stress, apoptosis signalling and cardiac

biomarkers against doxorubicin-induced

cardiotoxicity. Clin Exp Hypertens. 2019 Oct 20:1-12

[Epub ahead of print].

12. Hayakawa I, Okubo Y, Nariai H, et al. Recent treatment

patterns and variations for pediatric acute

encephalopathy in Japan. Brain Dev. 2020;42(1):48-55.

13. Huang C, Liao G, Han J, et al. Edaravone suppresses

degradation of type II collagen. Biochem Biophys Res

Commun. 2016;473(4):840-844.

14. Kabra A, Sharma R, Kabra R, Baghel US. Emerging and

alternative therapies for Parkinson disease: An

updated review. Curr Pharm Des. 2018;24(22):2573

2582.

15. Kassab AA, Aboregela AM, Shalaby AM. Edaravone

attenuates lung injury in a hind limb ischemia

reperfusion rat model: A histological,

immunohistochemical and biochemical study. Ann

Anat. 2020;228:151433.

16. Kobayashi S, Fukuma S, Ikenoue T, et al. Effect of

edaravone on neurological symptoms in real-world

patients with acute ischemic stroke. Stroke. 2019;50

(7):1805-1811.

17. Koike N, Sasaki A, Murakami T, Suzuki K. Effect of

edaravone against cisplatin-induced chronic renal

injury. Drug Chem Toxicol. 2019 May 7:1-10 [Epub

ahead of print].

18. Kong Z, Jiang J, Deng M, et al. Edaravone reduces

depression severity in patients with symptomatic

intracranial stenosis and is associated with the serum

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expression of sex hormones. Medicine (Baltimore).

2020;99(8):e19316.

19. Li H, Min J, Mao X, et al. Edaravone ameliorates

experimental autoimmune thyroiditis in rats through

HO-1-dependent STAT3/PI3K/Akt pathway. Am J Transl

Res. 2018;10(7):2037-2046.

20. Martinez A, Palomo Ruiz MD, Perez DI, Gil C. Drugs in

clinical development for the treatment of amyotrophic

lateral sclerosis. Expert Opin Investig Drugs. 2017;26

(4):403-414.

21. Masuda T, Shimazawa M, Takata S, et al. Edaravone is

a free radical scavenger that protects against laser-

induced choroidal neovascularization in mice and

common marmosets. Exp Eye Res. 2016;146:196-205.

22. Mitsubishi Tanabe Pharma Corporation. Radicut

Injection 30 mg. The Japanese Pharmacopoeia

Edaravone Injection. Prescription Drug. Package Insert

[English translation]. Standard Commodity

Classification No. of Japan 87119. Approval No.

21300AMZ00377000. 18th Version D15a. Osaka, Japan;

Mitsubishi Tanabe Pharma Corporation; Revised: June

2015.

23. Mitsubishi Tanabe Pharma Corporation. Radicava

(edavarone injection) for intravenous use. Prescribing

Information. 118839-W. Jersey City, NJ: Mitsubishi

Tanabe Pharma America; August 2017.



Information. Jersey City, NJ: Mitsubishi Tanabe Pharma

America; August 2018.



Information. Jersey City, NJ: Mitsubishi Tanabe Pharma

America; July 2019.

26. Naganuma M, Inatomi Y, Nakajima M, et al.

Associations between uric acid level and 3-month

functional outcome in acute ischemic stroke patients

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treated with/without edaravone. Cerebrovasc Dis.

2018;45(3-4):115-123.

27. Noto Y, Shibuya K, Vucic S, Kiernan MC. Novel

therapies in development that inhibit motor neuron

hyperexcitability in amyotrophic lateral sclerosis.

Expert Rev Neurother. 2016;16(10):1147-1154.

28. Oguro H, Mitaki S, Takayoshi H, et al. Retrospective

analysis of argatroban in 353 patients with acute

noncardioembolic stroke. J Stroke Cerebrovasc Dis.

2018;27(8):2175-2181.

29. Pan Y, Li W, Feng Y, et al. Edaravone attenuates

experimental asthma in mice through induction of

HO-1 and the Keap1/Nrf2 pathway. Exp Ther Med.

2020;19(2):1407-1416.

30. Parikh A, Kathawala K, Li J, et al. Self-nanomicellizing

solid dispersion of edaravone: Part II: In vivo

assessment of efficacy against behavior deficits and

safety in Alzheimer's disease model. Drug Des Devel

Ther. 2018;12:2111-2128.

31. Petrov D, Mansfield C, Moussy A, Hermine O. ALS

clinical trials review: 20 years of failure. Are we any

closer to registering a new treatment? Front Aging

Neurosci. 2017;9:68.

32. Radicava [package insert]. Jersey City, NJ: MT Pharma

America, Inc.; August 2018.

33. Sawada H. Clinical efficacy of edaravone for the

treatment of amyotrophic lateral sclerosis. Expert

Opin Pharmacother. 2017;18(7):735-738.

34. Tamer TM, Valachová K, Hassan MA, et al.

Chitosan/hyaluronan/edaravone membranes for anti-

inflammatory wound dressing: In vitro and in vivo

evaluation studies. Mater Sci Eng C Mater Biol Appl.

2018;90:227-235.

35. U.S. Food and Drug Administration. FDA approves

drug to treat ALS. FDA News. Silver Spring, MD: FDA;

May 5, 2017.

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36. Varatharajan R, Lim LX, Tan K, et al. Effect of

edaravone in diabetes mellitus-induced nephropathy

in rats. Korean J Physiol Pharmacol. 2016;20(4):333

340.

37. Wang B, Lin W. Edaravone protects against pancreatic

and intestinal injury after acute pancreatitis via

nuclear factor-κB signaling in mice. Biol Pharm Bull.

2020;43(3):509-515.

38. Writing Group; Edaravone (MCI-186) ALS 19 Study

Group. Safety and efficacy of edaravone in well

defined patients with amyotrophic lateral sclerosis: A

randomised, double-blind, placebo-controlled trial.

Lancet Neurol. 2017;16(7):505-512.

39. Wu Y. Clinical features, diagnosis, and treatment of

neonatal encephalopathy. UpToDate [online serial].

Waltham, MA: UpToDate; reviewed August 2019.

40. Yang J, Cui X, Li J, et al. Edaravone for acute stroke:

Meta-analyses of data from randomized controlled

trials. Dev Neurorehabil. 2015;18(5):330-335.

41. Zhang M, Teng CH, Wu FF, et al. Edaravone attenuates

traumatic brain injury through anti-inflammatory and

anti-oxidative modulation. Exp Ther Med. 2019;18

(1):467-474.

42. Zhang X, Ye G, Wu Z, et al. The therapeutic effects of

edaravone on collagen-induced arthritis in rats. J Cell

Biochem. 2020;121(2):1463-1474.

43. Zheng C, Liu S, Geng P, et al. Efficacy of edaravone on

coronary artery bypass patients with myocardial

damage after ischemia and reperfusion: A meta

analysis. Int J Clin Exp Med. 2015;8(2):2205-2211.

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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan

benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,

general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care

services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors

in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely

responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is

subject to change.

Copyright © 2001-2020 Aetna Inc.

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AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment to Aetna Clinical Policy Bulletin Number: 0918 Edaravone

(Radicava)

The Site of Care Utilization Management Policy does not apply to Edaravone (Radicava) for the Pennsylvania Medical Assistance Plan.

Continuation Criteria:

Aetna considers continued use of edaravone medically necessary when the following criteria are met:

• Diagnosis of definite or probable ALS; and • There is a clinical benefit from edaravone therapy; and • Continuous use of invasive ventilatory support is not required.

www.aetnabetterhealth.com/pennsylvania revised 07/21/2020

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http://www.aetnabetterhealth.com/pennsylvania

Documents

0918 Edaravone (Radicava) (3)